A mini-review-cancer energy reprogramming on drug resistance and immune response

Highlights • This review summarized the prominent cancer metabolic reprogramming on macromolecules.• In addition, metabolic reprogramming explaining immune response and treatment resistance as well as energy reprogramming mechanisms are briefly discussed.• Finally, some prospects in MR for reversing cancer drug resistance are highlighted.


Introduction
In 2020 alone, almost 10 million cancer related deaths was registered, making it as one of the leading causes of death worldwide.This multifactorial health burden despite the technology, the fight still persists [1].Cancer energy metabolism that involved mitochondria plays a key role in cancer drug resistance of the hypoxic tumor microenvironment (TME) in cancer cells.With the increasing evidence on immune escape, activation and immune cell metabolism, immunotherapy strategies can be designed on targeting mitochondria [2].Among the emerging approaches to curb treatment resistance in cancer, targeting metabolism is an effective strategy.Rewiring metabolism in cancer influences tumor-tumor-infiltrating immune cells.Through the modulation of oncogene-targeting, both memory T cells persistence and activation of lymphocytes lead to improved immune-surveillance [3].
With the TME functions, sensitive cells become immune resistance with tumor disease progression [4].Although there are evidences on metabolic reprogramming (MR) as literature, the recent summation of these findings that could send an informed consent to the researchers regarding the forms of energy reprogramming and the resulting drug resistance is limited.This mini review aimed to shed some lights on the forms of MR inducing the energy metabolism that modulate resistant treatment options for targeted therapy.

Metabolic reprogramming and treatment resistance
Extracellular vesicles (EVs) as key to drug resistance promote cancer cell proliferation while sustaining angiogenesis, cell invasion, metastasis, MR thus, enabling mutations and modulation of TME [5,6].In addition, EVs sustain resistance to cancer cell death, reprogram energy Abbreviations: ATP, adenosine triphosphate; DCA, dichloroacetate; DNMTs, DNA methyltransferases; EMT, epithelial-mesenchymal transition; eATP, extracellular ATP; EVs, extracellular vesicles; FASN, fatty acid synthase; HBP, hexamine biosynthesis pathway; HDACs, histone deacetylases; HIF-1, hypoxia-inducible factor-1; HRE, hypoxia response elements; IDH, Isocitrate dehydrogenase; IF1, inhibitory factor 1; MR, metabolic reprogramming; mTOR, rapamycin; MDSC, myeloid-derived suppressor cells; mtROS, mitochondrial reactive oxygen species; NAD, nicotinamide adenine dinucleotide; NAMPT, nicotinamide phosphoribosyltransferase; NPC, nasopharyngeal carcinoma; PXPHOS, oxidative phosphorylation; PC, pancreatic cancer; PTM, protein post-translational modification; metabolism to acquire genome stability [7].Nearly every characteristic of tumors, including angiogenesis, immune-escape, treatment resistance, and cell proliferation and metastasis, have been linked to tumor-derived EVs.Therapy-resistant cancer cells produce EVs which transfer their genetic material and glycolytic enzymes to sensitive cancer cells.This boosts chemotherapy metabolism, lowers ROS, and improves glycolysis, all of which contribute to treatment resistance.Purine metabolites, genetic material, and glycolytic enzymes that polarize macrophages to tumor-associated macrophages (TAMs) are carried and delivered by EVs, and these factors, directly impair the immune response to cancer [8].In this light, once EVs signaling networks are hijacked, it will lead to anti-tumor for a variety of cancers through obstructing malignant communications.In addition to glycolysis and oxidative phosphorylation, MR is a key process that facilitates HIF target genes functions [9].Although HIFs induced resistance has a very limited literature, phytochemicals and chemotherapy are promising for patients with HIF-1-independent drug resistance mechanisms [10].
HIF-1α/estrogen-related receptor α (HIF-1α/ERRα) promotes pyroptosis resistance and enhances tumor growth adaptation [11].Through aerobic glycolysis as the main pathway, cancer cells energy reprogramming is utilizing anabolic functions for metabolic energy.One specific MR is the upregulation of ATPase inhibitory factor 1 (IF1), the inhibitor of the H + -ATP synthase [12].Limiting ATP production, overexpression of IF1 enhances glycolysis through energy reprogramming metabolism.The mitochondrial reactive oxygen species (mtROS) that modulates the pathway signaling molecule for cellular proliferation and invasion is promoted, thereby modulating tumor immune response and thus resistance to cell death.A diverse nutritional supplement and reduced pH value is induced by nasopharyngeal carcinoma (NPC) [13].This is evident with tumor-infiltrating TME that incorporate fibroblast, immune cells and endothelial cells to facilitate immunosuppression and progression of cancer.The associating treatment resistance can be checked through MR and immune system study.TME in some cancers for instance, pancreatic cancer (PC) enables treatment resistance in addition to tumor growth, metastasis and immune response suppression.Cancer spread and disease lapses are strongly associated with PC increased resistance with distinct metabolic properties [14].Although not conclusive, bladder cancer associated with increased drug resistance is studied to be influenced by type I transmembrane protein, MUC1 through immune cell infiltration and metabolism [15].Importin-β facilitates the import of MUC1-C homodimers into the nucleus where it interacts with various transcription factors (TFs) including WNT/β-catenin/TCF4, NF-κB, NOTCH, and MYC, to promote epigenetic reprogramming, and epithelial-mesenchymal transition (EMT) process.These processes support immune evasion and DNA damage resistance [16].
Warburg effect as a key cancer progression machinery is an active metabolic reprogramming [17].Warburg effects defined a unique TME, which is epigenetically cooperated with hypoxia-inducible factor-1 (HIF-1) [18].Its effect emerged from HIF-1 overexpression (normoxic or hypoxic) as well as oncogene activation especially with cMyc, Ras.Under hypoxic conditions, HIF-1α accumulates and subsequently moves into the nucleus and form a complex with HIF-β that binds to hypoxia response elements (HRE) in the promoter region of genes engaged in angiogenesis, survival and proliferation.In addition, it affirms oncogene activation and loss of function of tumor through adenosine triphosphate (ATP) generation, diversion of glycolytic intermediates, inhibition of pyruvate, accumulation of lactate and glycolytic fluxes acceleration [19].In addition to the 6 biological process as the hallmark of cancer such as cell proliferation, evasion of growth suppressors, resistance, immortality, angiogenesis, invasion and metastasis, the RE-1 silencing transcription factor or neuron restrictive silencing factor NRSF/REST are essential targets for cancer therapy [20].
Under covering the carbon and glucose utilization as an alternative source for cancer growth explained mitochondrial oxidative phosphorylation (OXPHOS) metabolism [21].OXPHOS revealed the interplay between immune cells, neoplastic cells and stroma to participate in resistance to treatments through tumorigenesis [22].Another metabolic reprogramming associated with the immune cell microenvironment are carbohydrate and lipid pathways, forming a crucial prognosis for gynecological cancer [23].MR and therapeutic resistance depend on multiple processes, notably cancer metabolism, the expression of cancer genes, their epigenetic modifications and the energy requests of TME.
Although there has been evidence to support the Warburg effect, the cancer drug resistance detecting biomarkers are still missing.For melanoma progression, nicotinamide phosphoribosyltransferase (NAMPT) as an energy limiting enzyme of nicotinamide adenine dinucleotide (NAD) metabolism is now studied for its role in targeted therapy resistance [24].NAMPT transcription and NAD metabolism are enhanced by the activation of the BRAF-mutated pathway.Elevated NAMPT and NAD concentrations support an energy metabolism and fuel drug resistance processes.In addition, rapamycin (mTOR) pathway as a mammalian target can regulate functions of melanoma cell anabolism and energy metabolism and these are evident for both resistance and sensitive therapy.Treatment resistance in cancer is induced by immunosuppression and antitumor immunity impairment.This is significantly prominent with tumor progression through MR dynamics with distinct immune responses leading to a new emerging discipline called immunometabolism.In addition to metabolic display, nutrient competition existing between infiltrating immune cells and tumor cells confers explanations to antitumor immunity [25] (Fig. 1 and Table 1).

Metabolic reprogramming immune response
In cancer research immunometabolism can shift the metabolic competition to the favor of immune cells, reverse treatment resistance and initiate anti-tumor mechanisms during the treatment [39].MR resulting from TME affects both the immune cells and their immunosurveillance, thereby checking the cancer treatment resistance [40].TME acidity regulates tumor immunity through influencing immune cells metabolism, thus contributing to the systemic immunity and enhancing tumor progression and subsequently therapeutic resistance.Among the immune cells include myeloid-derived suppressor cells (MDSC) are TAMs and dendritic cells [41].Moreover, antitumor immune responses face resistance due to oncogenic signaling [42].
Hypoxia from excessive tumor growth regulate TME in the favor of cancer such as enhanced glycolysis in producing metabolites for cancer cells [43].Both fatty acids and glutamine uptake are increased due to hypoxic cancer cells metabolism as in hexosamine biosynthesis pathway (HBP).The resulting signaling pathway called protein post-translational ▪ Low-and heavy-load resistance exercise elicited similar acute responses in arm swelling and breast cancer-related lymphedema symptoms in women at risk for lymphedema receiving adjuvant taxane-based chemotherapy. [ Resistance exercise program in women treated for premenopausal breast cancer ▪ RCT ▪ Bone turnover markers decreased.
▪ No prevent bone loss among women.[37] Chronic lymphocytic leukemia and treatment resistance

▪ Experimental (in vivo)
▪ Transcriptional downregulation of pathways mediating energy metabolism.
▪ Early treatment period is important drug-resistant.[38] C. Liu et al.
modification (PTM) releases UDP-GlcNAc as the end product to facilitate tumor progression [44].Such metabolic changes in TME affect tumor immune cells through tumor immunosuppressive microenvironment thereby inducing resistance to immunotherapy [45].

Cancer metabolic reprogramming on macromolecules
As a precursor of gluconeogenesis, the glycolysis end product lactate is also a signaling molecule.Both cancer progression of cancer and the associated drug resistance are epigenetically linked to lactate reprogrammed energy input.These changes are ascribed in histone lysine lactylation and lactate-induced histone modification [46].Therapeutic resistance through altered amino acid metabolism leads to tumor outgrowth as described in immune response.Immune cell differentiations are triggered through amino acid metabolic enzymes such as GCN2 and mTOR.Therefore, it will be a metabolic advantage for cells against cancer cells through amino acid energy rewiring through targeting enzymes and their sensors [47].
As a selfish metabolic mechanism, cancer cells switch to abnormal metabolism thereby initiating energy tradeoffs between its essential function and resistance.One specific with growing attention is the lipid where choline metabolism has enough mechanism for resistance through the phosphatidylcholine cycle.In the prospective cancer research, phosphatidylcholine metabolism as in response to stress will shed some light to cancer therapy resistance [48].Phosphatidylcholine source of energy also forms an integral part of cell membrane constituents.This lipid plays a key role in cellular communication between immune cells and cancer cells in TME.To this end, an immune regulatory mechanism is conferred by this lipid in therapeutic functions [49].

Prospects in metabolic reprogramming for reversing drug resistance
The increased production of lactate is also prominent for nitric oxide, prostaglandins and ROS as well as arachidonic acid metabolism.These energy metabolism influence both TAMs and TME thus tumor cell metabolism.TAM will eventually lead to production of angiogenic factors and cytokines that contribute to the progression of tumor growth and metastasis.Understanding TAMs recruitment of these processes can help to potentiate anti-tumor and reversing treatment resistance therapy [50].A master regulator for cellular response against xenobiotic and oxidative stress, the system of Keap1-Nrf2 induces metabolic reprogramming thereby making a highly regarded anti-resistance therapeutic strategy [51].
There is an innovative approach that revealed advanced strategies on pro-inflammatory extracellular ATP (eATP) [26].Increased eATP potentiate antigen capacity of DCs to enable NK cells and T cells functions.This is done through driving macrophages pyroptosis from P2 × 7-NLRP3-inflammasome activation.Subsequently, tumor progression is suppressed through the synergistic antitumor immune response thereby inhibiting distant metastases and reverse anti-PD1 resistance.The most promising for cancer biochemistry in quest for rapid and non-recurrent, non-treatment resistance cancers is the mechanistic study of the association between tumor immunity and MR and the therapeutic strategy [52].For instance, there should be guidelines to interpret autophagy and related processes.Autophagy based therapy has growing prospects in overcoming tumor resistance to treatment strategies [53].T cell energy reprogramming can reverse T cell dysfunction and check treatment resistance to the number of cancer types [54].The directives involving cancer stem cells to dictate TME in their favors via growth factors releases, chemokines and cytokines promote neo-angiogenesis could be explored for harnessing treatment failures due to tumor drug resistance [55].
The ability of cancer cells to modify their metabolism in order to sustain fast growth and survival is known as MR, and it frequently leads to treatment resistance.Targeting glycolysis, TCA cycle, lipid metabolism, mitochondria metabolism, cancer cell dependencies, metabolic epigenetic regulations, nutrient availability in the TME and immunometabolism are some significant prospects and approaches for drug resistance reversal via MR.Even in the presence of oxygen, many cancer cells use glycolysis as a source of energy (the Warburg effect), thus, interfering with this metabolic route by using glycolysis inhibitors like dichloroacetate (DCA) and 2-deoxyglucose (2-DG) may be able to reverse resistance.Isocitrate dehydrogenase (IDH) and fumarate hydratase are two important TCA cycle enzymes that can be targeted to disrupt metabolic pathways that are essential for resistant cancer cells.Fatty acid production is frequently upregulated in cancer cells.Fatty acid synthase (FASN) inhibitors have the ability to decrease lipid availability, which might hinder energy storage and the formation of cell membranes.By targeting pathways related to oxidation (CPT1 inhibitors) and lipid uptake (CD36 inhibitors), cancer cells' metabolic flexibility can be decreased, increasing their susceptibility to chemotherapy treatments.It is common to find that cancer cells are dependent on specific amino acids, like glutamine.Cancer cells can be starved of glutamine, which is necessary for the production of nucleotides and proteins, using glutaminase inhibitors (CB-839).Drug-resistant metabolic adaptations can be reversed by focusing on epigenetic changes that control metabolic gene expression.For example, drugs that block DNA methyltransferases (DNMTs) or histone deacetylases (HDACs) may restore chemotherapy efficacy.Improving immune cells' (like T cells') metabolic fitness with metabolic modulators can strengthen their capacity to combat cancer cells.In addition, anti-tumor immune responses can be boosted by combining metabolic therapies with immune checkpoint inhibitors such as anti-PD-1/PD-L1 (Fig. 2).

Conclusion
It is apparent that strong evidence is now emerging to confer progress on the recent cancer treatment strategies and prevention based on MR.This change in energy acquisition is studied with promising explanations to distinct mechanisms of cancers, especially the types that pose treatment resistance.To this end, targeted therapies to reverse drug resistance mechanisms should be based on the metabolism influenced by cancer TME.

Fig. 1 .
Fig. 1.Metabolic reprogramming treatment resistance and immune escape processes in cancer cells.

Fig. 2 .
Fig. 2. Various prospects in metabolic reprogramming for reversing treatment resistance in cancers.

Table 1
Cancer energy reprogramming on drug resistance and immune response.